Weaver syndrome

What is Weaver syndrome?

Weaver syndrome is a disorder characterized by skeletal abnormalities and developmental delay. It is considered an overgrowth syndrome because the bones of affected individuals grow and develop more quickly than usual (advanced bone age) both before and after birth. Adult height is typically normal to tall.

In addition to advanced bone age, people with Weaver syndrome may have other skeletal abnormalities, including foot deformities; permanently bent joints, especially those in the fingers (camptodactyly); and broad thumbs. Characteristic features of the head and face include a large head (macrocephaly); flattened back of the head (occiput); a broad forehead; widely spaced eyes (hypertelorism); large, low-set ears; a long, deep groove in the area between the nose and mouth (philtrum); a dimpled chin; and a small lower jaw (micrognathia).

Individuals with Weaver syndrome have a weak, hoarse cry as newborns and delayed development of motor skills such as sitting, standing, and walking in early childhood. They typically have mild intellectual disability and poor coordination and balance. Some affected individuals have abnormalities in the folds (gyri) of the brain, which can be seen by medical imaging. Increased muscle tone (hypertonia); loose, saggy skin; and a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia) may also occur in this disorder. People with Weaver syndrome have an increased risk of developing cancer, but the small number of affected individuals makes the exact risk difficult to determine.

How common is Weaver syndrome?

The prevalence of Weaver syndrome is unknown. About 30 cases have been described in the medical literature.

What genes are related to Weaver syndrome?

Weaver syndrome is usually caused by mutations in the EZH2 gene; rare cases associated with mutations in the NSD1 gene have also been reported. The EZH2 gene provides instructions for making a type of enzyme called a histone methyltransferase. Histone methyltransferases modify proteins called histones, which are structural proteins that attach (bind) to DNA and give chromosomes their shape. By adding a molecule called a methyl group to histones (methylation), histone methyltransferases can turn off (suppress) the activity (expression) of certain genes, which is an essential process in normal development. Specifically, the EZH2 enzyme forms part of a protein group called the polycomb repressive complex-2. By turning off particular genes, this complex is involved in the process that determines the type of cell an immature cell will ultimately become (cell fate determination). Mutations in the EZH2 enzyme may disrupt methylation and impair regulation of certain genes in many of the body's organs and tissues, resulting in the abnormalities characteristic of Weaver syndrome.

The NSD1 gene provides instructions for making a protein whose full range of functions is unknown. Researchers believe that this protein controls the expression of certain genes involved in normal growth and development, and can turn genes on or off as needed. The mutations apparently impair the normal regulation of gene expression. A few individuals with NSD1 gene mutations have been diagnosed with Weaver syndrome. However, some researchers believe that these cases should be classified as unusual presentations of a similar disorder called Sotos syndrome, which is caused by NSD1 gene mutations.

How do people inherit Weaver syndrome?

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Almost all cases result from new mutations in the gene and occur in people with no history of the disorder in their family. In a small number of cases, an affected person inherits the mutation from one affected parent.

Where can I find information about diagnosis or management of Weaver syndrome?

These resources address the diagnosis or management of Weaver syndrome and may include treatment providers.

The resources on this site should not be used as a substitute for
professional medical care or advice. Users seeking information about
a personal genetic disease, syndrome, or condition should consult with a qualified
healthcare professional.
See How can I find a genetics professional in my area? in the Handbook.